PROJECT SUMMARY Primary Amebic Meningoencephalitis (PAM), caused by a free-living ameba Naegleria fowleri, has a fatality rate of over 97%. Though considered rare (but likely underreported), it is an infection with high mortality. There are no FDA-approved drugs to treat PAM. The CDC recommends the use of the antifungal drug amphotericin B and an antileishmanial drug miltefosine but few patients treated with the combination therapy have survived. Therefore, development of efficient drugs is a critical unmet need to avert future deaths. Because this is a rare disease, there is a paucity of drug discovery efforts by the pharmaceutical industry and drug discovery for this infection largely relies on academic research centers. Our preliminary studies identified HMG-CoA reductase (HMGR) inhibitors or statins as amebicidal against N. fowleri; cell biological studies provided evidence that these inhibitors targeted parasite HMGR. Identification of novel HMGR inhibitors targeting individual molecular target and combination of target-based approach with phenotypic activity laid the foundation for this proposal. Based on our preliminary data, we propose 1) to test statins against parasite recombinant HMGR, 2) to conduct tolerability and pharmacokinetic-pharmacodynamic studies of two promising blood-brain barrier permeable statins and 3) to test in vivo efficacy of these two statins in an animal model of PAM. The identification of blood-brain barrier permeable HMGR inhibitors and combination of biochemical and parasitological expertise will produce new antimicrobials that are suitable for the treatment of PAM.